The present disclosure provides, among other things, compounds comprising cyclic dinucleotides containing a 2',5' linkage useful in the design of research tools, as research tools, and as therapeutic modalities such as enzyme modulators.
Legal claims defining the scope of protection, as filed with the USPTO.
1. A compound of Formula II: or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from the group consisting of: Ring B is selected from the group consisting of: each X 1 and X 2 is independently —CR— or —N—; X 3 is —C(R) 2 —, —O—, or —NR—; X a and X b are independently —C(R) 2 —, —C(R)═C(R)—, —O—, —S—, —S(O)—, —S(O) 2 —, or —N(R)—; X a1 and X b1 are —C(R)—; X c and X d are independently oxygen, sulfur, a substituted nitrogen atom, BH 3 , or optionally substituted C 1-12 aliphatic, provided at least one of X c and X d is sulfur, a substituted nitrogen atom, BH 3 , or optionally substituted C 1-12 aliphatic; each X c and X f is independently —O—, —S—, or —N(R)—; each W is P; each R 1 and R 2 is independently selected from the group consisting of hydrogen, halogen, —NO 2 , —CN, —OR a , —SR, —N(R) 2 , —C(O)R, —CO 2 R, —C(O)C(O)R, —C(O)CH 2 C(O)R, —S(O)R, —S(O) 2 R, —C(O)N(R) 2 , —SO 2 N(R) 2 , —OC(O)R, —N(R)C(O)R, —N(R)N(R) 2 ,—N(R)C(═NR)N(R) 2 , —C(═NR)N(R) 2 , —C═NOR, —N(R)C(O)N(R) 2 , —N(R)SO 2 N(R) 2 , —N(R)SO 2 R, —OC(O)N(R) 2 , and optionally substituted C 1-12 aliphatic or C 1-4 alkoxy-C 1-4 alkyl; each R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , and R 11 is independently selected from the group consisting of hydrogen, halogen, —NO 2 , —CN, —OR, —SR, —N(R) 2 , —C(O)R, —CO 2 R, —C(O)C(O)R, —C(O)CH 2 C(O)R, —S(O)R, —S(O) 2 R, —C(O)N(R) 2 , —SO 2 N(R) 2 , —OC(O)R, —N(R)C(O)R, —N(R)N(R) 2 , —N(R)C(═NR)N(R) 2 , —C(═NR)N(R) 2 , —C═NOR, —N(R)C(O)N(R) 2 , —N(R)SO 2 N(R) 2 , —N(R)SO 2 R, —OC(O)N(R) 2 , or an optionally substituted group selected from C 1-12 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R 8 and R 9 , when present, is independently selected from the group consisting of hydrogen, halogen, —NO 2 , —CN, —OR′, —SR, —N(R) 2 , —C(O)R, —CO 2 R, —C(O)C(O)R, —C(O)CH 2 C(O)R, —S(O)R, —S(O) 2 R, —C(O)N(R) 2 , —SO 2 N(R) 2 , —OC(O)R, —N(R)C(O)R, —N(R)N(R) 2 , —N(R)C(═NR)N(R) 2 , —C(═NR)N(R) 2 , —C═NOR, —N(R)C(O)N(R) 2 , —N(R)SO 2 N(R) 2 , —N(R)SO 2 R, —OC(O)N(R) 2 , and optionally substituted C 1-12 aliphatic; each R is independently selected from the group consisting of hydrogen or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or: two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated, partially unsaturated, or heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and R a is an oxygen protecting group or R, wherein each optionally substituted group is: independently optionally substituted on a substitutable carbon atom with one or more of halogen, C 1-6 alkyl, —OR o , —SR o , or —N(R o ) 2 , wherein each R o is independently hydrogen or C 1-6 alkyl; or independently optionally substituted on a substitutable nitrogen atom with one or more of C 1-6 alkyl, —C(O)R † , —C(O)OR † , —S(O) 2 R † , or —S(O) 2 NR † 2 , wherein each R † is independently hydrogen or C 1-6 alkyl.
2. The compound of claim 1 , wherein Ring A is selected from the group consisting of:
3. The compound of claim 2 , wherein R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, —OR a , or —NH 2 .
4. The compound of claim 3 , wherein each R 3 , R 5 , and R 7 is independently selected from the group consisting of hydrogen and halogen, and wherein each R 4 and R 6 is independently selected from the group consisting of hydrogen, halogen, and —NH 2 .
5. The compound of claim 4 , wherein each X 1 is —N—, each X 2 is —N—, and each X 3 is —NH—.
6. The compound of claim 5 , wherein each X c and X f is —O—; X a and X b are —O—; and X a1 and X b1 are —CH—.
7. The compound of claim 6 , wherein R 10 and R 11 are hydrogen, and wherein the subindex of the carbon atoms to which each R 8 and R 9 is attached is 0.
8. The compound of claim 7 , wherein R a is R, and each R is hydrogen.
9. The compound of claim 8 , wherein one of X c and X d is sulfur.
10. The compound of claim 9 , wherein one of X c and X d is sulfur, and the other of X c and X d is oxygen or sulfur.
11. The compound of claim 10 , wherein X c and X d are both sulfur.
12. The compound of claim 1 , wherein: Ring A is selected from the group consisting of: X 3 is —C(R) 2 —or —NR—; X a and X b are independently —C(R) 2 —, —O—, —S—, —S(O)—, or —S(O) 2 —; X c and X d are independently oxygen, sulfur, a substituted nitrogen atom, BH 3 , or optionally substituted C 1-12 aliphatic, provided at least one of X c and X d is sulfur, a substituted nitrogen atom, or BH 3 ; each R 1 and R 2 is independently selected from the group consisting of hydrogen, halogen, —CN, —OR a , —N(R) 2 , —OC(O)R, —OC(O)N(R) 2 , and optionally substituted C 1-12 aliphatic; each R 3 , R 4 , R 5 , R 6 , R 7 , R 10 and R 11 is independently selected from the group consisting of hydrogen, halogen, —CN, —OR, —SR, —N(R) 2 , —C(O)R, —C(O)N(R) 2 , —N(R)C(O)R, and optionally substituted C 1-12 aliphatic; each R is independently selected from the group consisting of hydrogen, optionally substituted C 1-6 aliphatic, and optionally substituted phenyl; and the subindex of the carbon atoms to which each R 8 and R 9 is attached is 0.
13. The compound of claim 12 , wherein each optionally substituted group of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 11 and R is independently optionally substituted with one or more of halogen, C 1-6 alkyl, —OR o , —SR o , or —N(R o ) 2 , wherein each R o is independently hydrogen or C 1-6 alkyl.
14. The compound of claim 13 , wherein: each X 1 and X 2 is independently —CR— or —N—, wherein each R is independently hydrogen or C 1-6 aliphatic; X 3 is —NH—; X a and X b are independently —O— or —S—; X a1 and X b1 are independently —CH—; each X c and X f is independently —O—, —S—, or —NH—; each R 1 and R 2 is independently selected from the group consisting of hydrogen, halogen, —CN, —OR a , —N(R) 2 wherein each R is independently hydrogen or C 1-6 aliphatic, and C 1-12 aliphatic optionally substituted with one or more of halogen, —OR o , and —N(R o ) 2 ; each R 3 , R 4 , R 5 , R 6 , and R 7 is independently selected from the group consisting of hydrogen, halogen, —CN, —OR wherein R is hydrogen or C 1-6 aliphatic, —SR wherein R is hydrogen or C 1-6 aliphatic, —N(R) 2 wherein each R is independently hydrogen or C 1-6 aliphatic, —C(O)N(R) 2 wherein each R is independently hydrogen or C 1-6 aliphatic, —N(H)C(O)R wherein R is hydrogen, C 1-6 aliphatic, or phenyl, and C 1-12 aliphatic optionally substituted with one or more of halogen, —OR o , and —N(R o ) 2 ; each R 10 and R 11 is independently hydrogen or C 1-2 alkyl; R a is an oxygen protecting group, hydrogen, or C 1-6 aliphatic; and each R o is independently hydrogen or C 1-6 aliphatic.
15. The compound of claim 14 , wherein: each X 1 and X 2 is independently —CH— or —N—; one of X c and X d is sulfur, and the other of X c and X d is oxygen or sulfur; each X c and X f is —O—; each R 1 and R 2 is independently selected from the group consisting of hydrogen, halogen, —OR a , and —NH 2 ; each R 3 , R 4 , R 5 , R 6 , and R 7 is independently selected from the group consisting of hydrogen, halogen, —OR wherein R is hydrogen or C 1-6 alkyl, —SR wherein R is hydrogen or C 1-6 alkyl, —NH 2 , and —N(H)C(O)R wherein R is hydrogen, C 1-6 alkyl, or phenyl; and R a is an oxygen protecting group or hydrogen.
16. The compound of claim 1 , wherein the compound is of formula II-a: or a pharmaceutically acceptable salt thereof.
17. The compound of claim 16 , wherein the compound is of formula X, XIV, or XVI: or a pharmaceutically acceptable salt thereof.
18. The compound of claim 16 , wherein: Ring A is each X 1 is —N—; each R 3 and R 5 are hydrogen; each R 4 is —NH 2 ; X a and X b are —O—; X c and X f are —O—; R 1 and R 2 are —OH; X a1 and X b1 are —CH—; R 10 and R 11 are hydrogen; and R 8 and R 9 are hydrogen; or a pharmaceutically acceptable salt thereof.
19. The compound of claim 16 , wherein: Ring A is each X 1 is —N—; each R 3 and R 5 are hydrogen; each R 4 is —NH 2 ; X a and X b are —O—; X c and X d are sulfur; X c and X f are —O—; R 1 and R 2 are —OH; X a1 and X b1 are —CH—; R 10 and R 11 are hydrogen; and the subindex of the carbon atoms to which each R 8 and R 9 is attached is 0; or a pharmaceutically acceptable salt thereof.
20. A pharmaceutical composition comprising the compound claim 1 and a pharmaceutically acceptable carrier.
Cooperative Patent Classification codes for this invention. Click any code to explore related patents in that topic.
June 28, 2019
May 25, 2021
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